S100A8/A9-amplified inflammation (TNF-α/IL-1β) in the bone marrow of tumor-bearing host disrupts early B cell development

Solid tumors induce systemic immune suppression, including impaired B lymphopoiesis in the bone marrow (BM). This study elucidates a novel mechanism by which remote tumors disrupt early B cell development. We demonstrate that tumor-bearing hosts exhibit skewed BM hematopoiesis favoring myeloid lineages at the expense of lymphoid lineages, specifically B cells. This impairment originates at the Common Lymphoid Progenitors (CLPs) stage. Mechanistically, monocytes, particularly CXCR2⁺ monocytes within the BM of tumor bearing mice leads to significantly elevated secretion of inflammatory cytokines TNF-α and IL-1β. These cytokines suppress CLPs differentiation into B cells. Furthermore, the enhanced secretion of TNF-α and IL-1β is mainly amplified by elevated levels of myeloid-derived S100A8/A9 proteins in the tumor-bearing BM microenvironment. Collectively, these findings identify the S100A8/A9 / TNF-α/IL-1β axis as a critical pathway disrupting B lymphopoiesis in cancer, revealing potential therapeutic targets to restore immune competence and improve immunotherapy responses.